Current therapies for chronic or acute pain are often either ineffective and/or have substantive risks relative to the benefits. To date, it is difficult to find reliable and satisfactory methods for addressing either chronic or acute pain in patients that fail to resolve that pain in such a way that they heal and achieve a feeling of well-being. Some of the more well-known therapeutics for pain involve the usage of: 1) the non-steroidal anti-inflammatory drugs or NSAID analgesics; 2) the morphine-related opioid analgesic class of drugs, such as oxycodone and hydromorphone; and 3) the usage of anti-depressants, for example the Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) and Selective Serotonin Reuptake Inhibitor (SSRI) classes of drugs including duloxetine, sertraline, venlafaxine, and fluoxetine, the tricyclic class of antidepressants; and cognitive behavioral therapy. However, all of these approaches suffer from either a lack of efficacy and/or unintended side effects that are frequently worse than the benefits. For example, the NSAID class of analgesics, when used for chronic pain over a period of time, can cause significant GI tract irritation. With respect to the opioid or morphine related class of drugs, recent data indicate that chronic usage can even be responsible for and induce pain by itself (Mao, J., “Opioid-induced Abnormal Pain Sensitivity,” Current Pain and Headache Reports, 2006, 10:67-70). In addition, side effects for opiates include nausea and vomiting, confusion, compromised immune function, subnormal testosterone levels in males leading to osteoporosis, addiction, lack of efficacy over time (tolerance), and constipation. The anti-depressants are well known in the clinical realm as having sexual dysfunction side effects, including arousal disorder, ejaculation failure and difficulty achieving orgasm, as well as an FDA mandated black box warning for increased risk of suicidality. Other common side effects for anti-depressants include nausea, insomnia, dizziness, tremor, and decreased libido.
The sex steroid hormones are normally considered to be important in the clinic for sexual health, but have never been used in routine practice or as standard therapy in the clinic to reduce chronic pain. Androgens, estrogens and progestins, or their agonists and antagonists, are used by reproductive endocrinologists within the clinic to treat sexual disorders. The use of these hormones are not normally thought of outside the context of sexual function such as reproduction and secondary sex traits. However, more recently, it has been recognized that estrogens, for example, are important in the health of men for bone plate formation (Smith et al., The New England Journal of Medicine, 1994, 331:1056-1061; Ohlsson and Vandenput, European J. of Endocrinology, 2009, 160:883-889). Likewise, it is plausible that androgens are important for overall health beyond their role in reproduction. The instant invention relates to the importance of healthy serum levels of testosterone for non-reproductive neuroendocrine health for reducing pain and/or increasing pain threshold, and to foster feelings of well-being. There is also accumulating evidence that the sex hormones, in particular estrogens, progestins, and now testosterone, can be correlated to subjective feelings of well-being and quality of life. In fact, either too high or too low levels of the sex steroid hormones, including testosterone, result in a loss of feeling of well-being. Specifically, testosterone can have an effect on dopamine, serotonin, N-methyl-D-aspartic acid (NMDA), and enkephalinergics, all of which contribute to feelings of well-being and modulation of mood. The best way to evaluate testosterone deficiency in the clinic is to look for clinical symptoms of too-low androgen levels in a human subject whose blood serum levels are in the lower half of the reference range.
Clinical symptoms of androgen insufficiency may include, but are not limited to, loss of libido, bouts of impotence, chronic fatigue, insomnia, hot flushes, sweating, alopecia or hair loss, mood change, mood swings, nervousness, loss of feelings of well-being, anemia such as that caused by insufficient erythropoietin production, impaired memory, inability to concentrate, Alzheimer's Disease (patients with androgen insufficiency have a higher risk), andropause (low production of androgens), night sweats, anovulatory menstrual cycles, amenorrhea, menorrhagia, menometrorragia, metrorrhagia, oligomenorrhea, polymenorrhea, decrease in muscle mass, osteoporosis, compression fractures, and obesity (unhealthy fat to muscle ratios). In addition, disorders such as diabetes, hypertension, Klinefelter's, Wilson-Turner and Androgen insensitivity syndromes can produce hypogonadism.
Acute vs. chronic pain. Acute pain is a sensation that is normally triggered in the nervous system to alert an individual about possible injury and the need to respond to the situation. Chronic pain is different. Chronic pain, usually inflammatory in nature, has been defined by the National Institute for Neurological Disorders and Stroke as persistent pain, which can last as long as six months or more. Here, pain signals keep firing in the nervous system for weeks, months, even years. There may have been an initial mishap, such as a sprained back, or serious infection, or there may be an ongoing cause of pain, such as arthritis, cancer, or an ear infection, but the nervous system inappropriately fails to dampen and thereby resolve the painful insult. Some people suffer chronic pain in the absence of any past injury or evidence of body damage. Temporal summation of pain and “wind-up” phenomena, whereby pain is amplified in intensity over time and the painful area increases in size, are thought to be involved, although the biologic mechanisms for controlling pain remain poorly defined. Furthermore, the reasons why some people are more susceptible to pain than others has not been well understood. Many chronic pain conditions affect older adults, but they are not limited to older adults. Common chronic pain complaints include headache, low back pain, cancer pain, arthritis pain, neurogenic pain (pain resulting from damage to the peripheral nerves or to the central nervous system itself), and so-called “psychogenic” pain (pain not due to past disease or injury or any visible sign of damage inside or outside the nervous system, but to psychological trauma, for example). Here we define pain as unresolvable chronic or acute inflammatory pain, or an abnormally low pain threshold due to stress/distress on/within the individual that is unresolvable.
There are numerous conditions that are accompanied with, or caused by pain, some of which involve chronic pain. There are also numerous theories relating to the treatment of chronic pain. Presently, there is extensive ongoing research relating to pain, how pain is transmitted through and perceived by the body, and treatments to overcome, or at least alleviate pain. The importance of receptors in the body and how some neurotransmitters function is being studied (See, e.g., Millan, 2000, Prog. Neurobiol. 66:255-474), although effective treatment of pain in the clinic remains problematic.
Stress on an individual can be resolved (“eustress”), but when stress is unresolvable by the individual (“distress”), it can be the basis of unresolvable pain. It is known that chronic pain can be the result of a wide variety of stressor conditions and stressor states, including disease, surgery, various types of trauma and/or physical distress. Emotional distress such as grief, and pathologic states within the immune system, nervous system, endocrine system, and other biologic systems can also act as stressor states that contribute to pain. Such stress can lead to unresolvable pain in both females and males. Selye defines stress as a “non-specific response of the body to any demand. A stressor is an agent that produces stress at any time.” (Selye, CMA Journal, 1976, 115:53-56 at 53). Selye's “general adaptation syndrome” recognizes three phases in an individual's resistance to stress: the initial alarm, resistance to that alarm, and if not resolved, exhaustion. Further, Selye coined the term “eustress” in which the individual responds to a stressor such that adaptation and coping responses resolve the stress, as opposed to “distress” in which the individual's stress response fails to be resolved. However, it is not well understood why, despite cognitive behavior modification training, for example, some individuals are able to adapt so much better than others, or why an individual who has previously been able to adapt can no longer do so. In other words, sometimes the individual can adapt to the stress such that the stress is resolved, while in other situations the individual cannot adapt, and the stress on the individual remains unresolved. When the stress is resolved, the result is a state of eustress. When the stress is unresolvable, the result is a state of distress and a lack of feeling of well-being, resulting in pain and/or illness. Part of the problem is our poor understanding of how the various neuroendocrine and immunologic pathways modulate our responses to stress, and promote or fail to promote eustress and feelings of well-being in an individual. It is not widely appreciated that stress, by itself, can catabolize and exhaust the body's supply of androgens, as exemplified by individuals studied during combat training (Opstad, P. K., et al., J. Clinical Endocrinology & Metabolism, 1992, 74:1176-83). The instant invention here is that androgen therapy can restore healthy serum levels of androgen and thereby ameliorate distress, can partially or completely resolve that stress, and can reestablish a state of eustress along with feelings of well-being. Further, androgen therapy that restores stress-depleted androgen levels to effective and safe levels, while providing significant clinical responses without clinical evidence of androgen excess, is driven largely by effective processing and dampening of pain, the mechanism for which is clearly laid out herein. Finally, in one embodiment, the instant invention encompasses the use of androgen therapy to enable stress to be processed and pain to be decreased.
Current treatment of unresolvable inflammatory pain. Treatment for chronic inflammatory pain includes some of the same treatments for acute pain, including opioids, non-opioid analgesics, and anti-inflammatory drugs. Treatment of chronic pain can also include additional approaches, such as, antidepressants, acupuncture, local electrical stimulation, and brain stimulation, as well as surgery. Some physicians use placebos, which in some cases has resulted in a lessening or elimination of pain. Psychotherapy, relaxation, and medication therapies, biofeedback, and behavior modification may also be employed to treat chronic pain.
Sex steroid hormones, notably androgens, can be important for pain processing. There is some evidence that both androgens and estrogens play a role in pain sensation in animal models, although this has not been adequately studied or approved in humans for chronic pain. Further, it appears that gender can have an impact on the sensation of pain. It is well known, for example, that testosterone decreases the production of sex hormone binding globulin (SHBG), while estradiol increases SHBG production. SHBG acts to sequester sex steroid hormones away from the bioavailable pool, preventing entry of sex steroid hormones across the blood-brain barrier (BBB) into the central nervous system. There is evidence that the blood-brain barrier is more permeable to testosterone than estradiol; in rodents, the fetus has a SHBG-like protein, fetoneonatal estrogen binding protein (alpha-fetoprotein) that is thought to act to sequester peripheral estrogen, but not testosterone, away from the central nervous system (MacLusky et al., Science, 1981, 211:1294). In addition, the concept that SHBG can prevent entry of sex hormones through the blood-brain barrier to the central nervous system has been shown in a human-into-rodent model (Pardridge W. M. et al. The American Journal of Physiology, 1980, 239:1 E103-E108). These findings are consistent with the theory that it is testosterone rather than 17-beta estradiol that most effectively transits from serum through the blood-brain barrier and into the central nervous system to mediate anti-nociception. It is the nociceptive relay neurons in the spinal cord that are well known to be important for transmitting pain signals, and conversely they can also be involved in dampening pain.
Gonadal or sex steroid hormones down-regulate inflammatory cell responses. It is well known that there is an inverse correlation between gonadal steroid hormones (estrogens, progestins and androgens) and inflammation. First, at puberty gonadal steroid hormone serum levels surge when the thymus correspondingly undergoes “involution,” in which there is decreased thymic cellularity, decreased thymic cell development, and decreased thymic cell output to the periphery as measured by recent thymic emigrants (RTE) (a good measure of peripheral thymic cells, also known as T cells or T lymphocytes, which are critical for inflammation). Second, during pregnancy, the acute surge in gonadal steroid hormone serum levels that occurs results in further thymic involution, and consequently greatly decreased numbers of peripheral thymocytes which would otherwise recognize the embryo as foreign and reject it. Concomitant with the decreased thymic T cell output in pregnancy is a high susceptibility to infection, for example the high risk of pregnant women to infection from rubella (measles), which can be abortogenic (which is in itself an inflammatory response that overcomes the mother's immunologic tolerance of the fetus, thereby rejecting it as foreign) or result in severe harm to the fetus. In fact, researchers use this increased susceptibility to infection in pregnancy to successfully infect animals with pathogens (pathogens which would otherwise be eliminated by the immune system) to create animal model systems for studying those pathogens. Third, gonadectomy (e.g., ovariectomy of animals) results in a reversal of thymic involution, restoration of thymic cellularity and thymic output, and an increased T cell repertoire (in both diversity and numbers) in the periphery (Perisic M. et al., “Role of ovarian hormones in age-associated thymic involution revisited,” Immunobiology, 2010, 215(4):275-293). Fourth, rescue of gonadectomy with exogenous hormone by injection of gonadal steroid hormones into animals decreases the numbers of thymocytes and T cells in the periphery (Zoller A. L. et al., “Murine pregnancy leads to reduced proliferation of maternal thymocytes and decreased thymic emigration,” Immunology, 2007 121(2):207-215).
Hormone replacement therapy in women has focused on estrogens and progestins, but not on androgens. The Women's Health Initiative (WHI) clinical trial, whose aim was to prospectively evaluate the risks and benefits of orally administered combination hormone replacement therapy in healthy women using estrogens and medroxyprogesterone acetate, was relatively recently halted (Fletcher, S. W., et al., J. Amer. Med. Assoc., 2002, 288: 366-368). The increased risks in coronary heart disease, breast cancer, stroke, and pulmonary embolism outweighed the increased benefits in colorectal cancer, endometrial cancer, hip fractures and death due to other causes, resulting in a small but statistically significant increased risk for the global index of hazard ratios among women taking these hormones. The authors pointed out, however, that their study only evaluated healthy women, not those with symptoms of hormone deficiency. This means that the treatments would have raised the serum levels of hormones to a level exceeding the normal levels of hormones for women of the same age. Furthermore, these treatments were orally administered. Other routes of delivery, e.g., transdermal systems, need to be studied, since it is possible that transdermal delivery may increase benefits and/or decrease risks to these patients. It was noted by the authors of the WHI study that hormone replacement therapy is still considered to be effective for relieving peri-menopausal symptoms such as hot flashes. Since the completion of the WHI trial, it has also been found that hormone replacement therapy has greater benefits and rare risks in women aged 50-59, a younger age group relative to the WHI trial (van de Weijer et al., Maturitas, 2008, 60:59). On Mar. 31, 2009, methyltestosterone combined with estrogens (Solvay's ESTRATEST®), prescribed to women for hot flashes when they failed to get relief from estrogen replacement therapy, was taken off the market because Solvay never demonstrated efficacy to the FDA. The FDA's new regulation system (Drug Efficacy Study and Implementation, DESI) required additional studies on ESTRATEST® to prove drug efficacy, which forced ESTRATEST® to fall under the unapproved drugs category on the FDA's DESI list.
Androgen therapy is effective against muscle wasting, for example in AIDS, but has not been approved to treat chronic inflammatory pain states. Most clinical trials evaluating sex hormone replacement therapy have focused on estrogens and progestins in women. Testosterone replacement therapy in individuals who may be testosterone deficient is now beginning to be addressed using transdermal delivery systems. For example, disease states in which there is loss of muscle mass may be treated with transdermal testosterone administration. This includes wasting syndrome in women with AIDS (Miller, K., et al., J. Clin. Endocrinol. Metab., 1998, 83:2717-2725; Javanbakht, M. et al., J. of Clinical Endocrinology & Metabolism, 2000, 85:2395-2401).
However, there is still an unmet need to develop therapeutic agents for pain that are both safe and effective, and with minimal adverse side effects, for chronic pain. In addition, there is a need to provide treatment for unresolvable chronic and acute pain that is often experienced by both females and males who are deficient in androgens, such as testosterone.